Use of phenoxy-piperzine derivatives

ABSTRACT

A method of treating or preventing illnesses caused by a disorder of the dopamine system. The method comprises administering to a host in need of such treatment or prevention an effective amount of a pharmaceutical composition comprising a compound of the formula ##STR1## wherein R 1  and R 3  each independently are hydrogen, aryl, carbamoyl, lower-alkyl-carbonyl, lower-alkyl, halogen, lower-alkyl-carbonyl-amino, lower-alkenyl-carbonyl-amino, amino, arylamino, aryloxy, nitro, aryl-acetyl, lower-alkanoyl-lower-alkyl, alkyl-sulphonyl-amino, ureido or furan-2-yl-carbonyl-amino and 
     R 2  is hydrogen, lower-alkyl, trifluoromethyl, halogen, lower-alkoxy, lower-alkyl-carbonyl or lower-alkyl-carbonyl-amino or 
     R 1  and R 2  together are --OCH 2  O--, --O(CH 2 ) 2  O-- or --(CH 2 ) 3  --, 
     R 4  is hydrogen, halogen, hydroxy, lower-alkyl, lower-alkoxy or nitro, 
     R 5  is hydrogen, halogen or lower-alkoxy, 
     R 6  is hydrogen, lower-alkyl, halogen, hydroxy, amino, lower-alkoxy, trifluoromethyl, nitro or lower-alkyl-carbonyl-amino and 
     R 7  is hydrogen or lower-alky-carbonyl, 
     or a pharmaceutically acceptable salt of a compound of formula I, and a pharmaceutically inert carrier material.

SUMMARY OF THE INVENTION

The invention is concerned with a method of treating or preventing illnesses caused by disorders of the dopamine system. The method comprises administering to a host in need of such treatment or prevention an effective amount of a pharmaceutical composition comprising a compound of the formula ##STR2## wherein R¹ and R³ each independently are hydrogen, aryl, carbamoyl, lower-alkyl-carbonyl, lower-alkyl, halogen, lower-alkyl-carbonyl-amino, lower-alkenyl-carbonyl-amino, amino, arylamino, aryloxy, nitro, aryl-acetyl, lower-alkanoyl-lower-alkyl, alkyl-sulphonyl-amino, ureido or furan-2-yl-carbonyl-amino and

R² is hydrogen, lower-alkyl, trifluoromethyl, halogen, lower-alkoxy, lower-alkyl-carbonyl or lower-alkyl-carbonyl-amino or

R¹ and R² together are --OCH₂ O--, --O(CH₂)₂ O-- or --, (CH₂)₃ --,

R⁴ is hydrogen, halogen, hydroxy, lower-alkyl, lower-alkoxy or nitro,

R⁵ is hydrogen, halogen or lower-alkoxy,

R⁶ is hydrogen, lower-alkyl, halogen, hydroxy, amino, lower-alkoxy, trifluoromethyl, nitro or lower-alkyl-carbonyl-amino and

R⁷ is hydrogen or lower-alkyl-carbonyl,

or a pharmaceutically acceptable salt of a compound of formula I, and a pharmaceutically inert carrier material.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula I and their salts are known and described in U.S. Pat. No. 3,701,777. The compounds of formula I and their salts can be prepared by methods known and described in U.S. Pat. No. 3,701,777, incorporated by reference herein.

As used herein, the term "lower alkyl" denotes straight or branched chain lower alkyl of 1 to 6 carbon atoms, for example, methyl, ethyl or isopropyl, butyl, pentyl and the like. The term "lower alkoxy" denotes alkyl ether groups in which the lower alkyl is as described above, for example, methoxy, ethoxy, isopropoxy, and the like. The term "halogen" denotes chlorine, bromine, fluorine and iodine. Of the halogens, fluorine and chlorine are prepared.

The amino group, is desired, can be substituted by lower alkyl of 1 to 6 carbon atoms, such as, for example, methyl-, ethyl-, propyl-, butyl-, or pentyl-amino and the like. The term "lower alkenyl" denotes straight and branched chain olefinic unsaturated hydrocarbon groups having from 2 to 6 carbon atoms. The term "aryl" denotes phenyl or phenyl bearing a lower alkyl of 1-4 carbon atoms. Of these, p-tolyl is preferred.

It has now surprisingly been found that compounds of formula I and their salts are useful in the control or prevention of illnesses which are caused by disorders of the dopamine system, for example, psychotic illnesses such as schizophrenia. The object of the present invention is accordingly the use of compounds of formula I or salts thereof for the treatment or prevention of psychotic illnesses which are caused by disorders of the dopamine system, in particular the dopamine-D₄ receptor.

The compounds of formula I and their salts have a high selective affinity to the dopamine-D₄ receptor. As a result use of the compounds of formula I or their salts results in significantly fewer side effects than would occur with the use of known classical neuroleptic agents, for example, haloperidol, which, as is known, bind to the D₂ or D₃ receptor. It has been found that in the case of schizophrenia the D₂ and D₃ receptor density increases by about 10%, while it can increase in the case of the D₄ receptor by about 600% (TiPS, July 1994, vol. 15, p. 264-70).

Compounds of formula I were characterized by their binding behavior at the D₄ receptor.

CHO cells (Chinese Hamster Ovary) were used in the test. Crude membranes were isolated by ultracentrifugation from D₄ -CHO and D₂ -CHO cells and were stored at -80° C. After thawing and homogenizing in a buffer solution (50mM Tris, 1 mM EDTA, 5 mM KCl, 1.5 mM CaCl₂, 4 mM MgCl₂, pH 7.4) they were incubated at room temperature for 90 minutes with 200 pM [³ H] spiperone and an increasing concentration (1×10⁻¹¹ M to 1×10⁻⁴ M) of test compound. A non-specific binding was established by incubating in the presence of 1×10⁻⁵ M (+)-butaclamol. The unbound radioligand was removed by filtration through a GF/C glass filter and the bound radioactivity was determined by scintillation in a Packard TopCount.

The following Table shows the binding behavior of some selected compounds at the D₄ receptor.

The Ki value, a binding constant which shows the affinity of the compounds to the D₄ receptor, was determined by known methods using ³ H-spiperone. The calculation of the value was effected with ligand.

                                      TABLE 1                                      __________________________________________________________________________                                            Ki at                                                                          D.sub.4                                 Cpd. No.                                                                            R.sup.1                                                                           R.sup.2                                                                           R.sup.3     R.sup.4                                                                          R.sup.5                                                                          R.sup.6                                                                               R.sup.7                                                                             [nM]                                    __________________________________________________________________________      1   H  H  H           H H H      H    <100                                     2   H  H  NH.sub.2    H H H      H    <100                                     3   H  H  COCH.sub.3  H H H      H    <100                                     4   H  H  CONH.sub.2  H H H      H    <100                                     5   H  CF.sub.3                                                                          H           Cl                                                                               H H      H    <100                                     6   H  H  NHCOCH.sub.3                                                                               H H CH.sub.3                                                                              H    <100                                     7   H  H  NHCOCH.sub.3                                                                               H H CF.sub.3                                                                              H    <100                                     8   H  H  NHCOCH.sub.3                                                                               H H OH     H    <100                                     9(+)                                                                               H  H  NH.sub.2    H H OCH.sub.3                                                                             H    <100                                    10(rac)                                                                             H  H  NHCOCH.sub.3                                                                               H H OCH.sub.3                                                                             H    <100                                    11(+)                                                                               H  H  NHCOCH.sub.3                                                                               H H OCH.sub.3                                                                             H    <100                                    12(-)                                                                               H  H  NHCOCH.sub.3                                                                               H H OCH.sub.3                                                                             H    <100                                    13   H  H  NHCOCH.sub.2 CH.sub.3                                                                      H H OCH.sub.3                                                                             H    <100                                    14   H  H  NHCO(CH.sub.2).sub.4 CH.sub.3                                                              H H OCH.sub.3                                                                             H    <100                                    15   H  H  NHCOC(CH.sub.3).sub.3                                                                      H H OCH.sub.3                                                                             H    <100                                    16   H  H  NHCOCHCHCH.sub.3                                                                           H H OCH.sub.3                                                                             H    <100                                    17   H  H                                                                                  ##STR3##   H H OCH.sub.3                                                                             H    <100                                    18   H  H  H.sub.2 NCONH                                                                              H H OCH.sub.3                                                                             H    <100                                    19   CH.sub.3                                                                          H  NHCOCH.sub.3                                                                               H H OCH.sub.3                                                                             H    <100                                    20   H  CH.sub.3                                                                          NHCOCH.sub.3                                                                               H H OCH.sub.3                                                                             H    <100                                    21   H  H  CH.sub.2 COCH.sub.2 CH.sub.3                                                               H H OCH.sub.2 CH.sub.3                                                                    H    <100                                    22   H  H  NH.sub.2    H H NO.sub.2                                                                              H    <100                                    30   H  H  NHCOCH.sub.3                                                                               H H OCH.sub.3                                                                             COCH.sub.3                                                                          <100                                    31(+)                                                                               H  H  NHCOCH.sub.3                                                                               H H OCH.sub.3                                                                             COCH.sub.3                                                                          <100                                    __________________________________________________________________________

The compounds set forth in Table 1 are:

1 1-Phenoxy-3-(4-phenyl-piperazin-1-yl)-propan-2-ol;

2 1-(2-Amino-phenoxy)-3-(4-phenyl-piperazin-1-yl)-propan-2-ol;

3 1-[2-[2-Hydroxy-3-(4-phenyl-piperazin-1-yl)-propoxy]-phenyl]-ethanone;

4 2-[2-Hydroxy-3-(4-phenyl-piperazin-1-yl)-propoxy]-benzamide; 1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-3-(3-trifluoro-methyl-phenoxy)-propan-2-ol;

6 N-[2-[2-Hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propoxy]-phenly]-acetamide;

7 N-[2-[2-Hydroxy-3-[4-(2-trifluoromethyl-phenyl)-piperazin-1yl]-propoxy]phenyl]-acetamide;

8 N-[2-[2-Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-propoxy]-phenyl]-acetamide;

9 [+]-1-(2-Amino-phenoxy)-3-[4(2-methoxy-phenyl)-piperazin-1-yl]-propan-2-ol;

10 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propoxy]-phenyl]-acetamide;

11 [+]-N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propoxy]phenyl]-acetamide;

12 [-]-N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propoxy]phenyl]-acetamide;

13 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propoxy]-phenyl]propionamide;

14 Hexanoic acid [2-[2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]propoxy]-phenyl]-amide;

15 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propoxy]-phenyl]-2,2-dimethyl-propionamide;

16 [+]-(E)-But-2-enolic acid [2-[2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propoxy]-phenyl]-amide;

17 Furan-2-carboxylic acid [2-[2hydroxy-3-[4-(2-methoxy-phenyl)piperazin-1-yl]-propoxy]-phenyl]-amide;

18 [2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]propoxy]-phenyl]-urea;

19 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-proxpoxy]-5-methyl-phenyl]-acetamide;

20 N-[2-[2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propoxy]-4-methyl-phenyl]-acetamide;

21 N-[2-[3-[4-(2-Ethoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propoxy]-phenyl]propionamide;

22 1-(2-Amino-phenoxy)-3-[4-(2-nitro-phenyl)-piperazin-1-yl]-propan-2-ol;

30 Ethyl 2-(2-acetylamino-phenoxy)-1-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]-acetate and

31 Ethyl [+]-2-(2-acetylamino-phenoxy)-1-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]acetate.

Compounds of formula I were compared with respect to their D₂ receptor activity.

The following Table 2 shows the selectivity of compounds of formula I with respect to the D₂ receptor, expressed by the ratio of the Ki values at the D₄ receptor and at the D₂ receptor.

                                      TABLE 2                                      __________________________________________________________________________     Comp.                          Ki at D.sub.4                                                                       Sel. vs.                                   No. R.sup.1                                                                           R.sup.2                                                                           R.sup.3  R.sup.4                                                                           R.sup.5                                                                          R.sup.6                                                                             R.sup.7                                                                          [nM] D.sub.2                                    __________________________________________________________________________     23  H  CH.sub.3                                                                          H        H  H H    H 9.6  300                                        24  H  H  --NHCOCH.sub.2 CH.sub.3                                                                 H  H H    H 29   233                                        25  H  H  --NHCOCH.sub.3                                                                          OH H --OCH.sub.3                                                                         H 10.2 1370                                       26  H  H  --NHSO.sub.2 CH.sub.3                                                                   H  H --OCH.sub.3                                                                         H 3.2  177                                        27  NO.sub.2                                                                          H  --NHCOCH.sub.3                                                                          H  H --OCH.sub.3                                                                         H 15   112                                        28  H  Br --NHCOCH.sub.3                                                                          H  H --OCH.sub.3                                                                         H 5.8  135                                        29  H  H  --NHCOCH.sub.3                                                                          H  H NO.sub.2                                                                            H 8.7  360                                        __________________________________________________________________________

The compounds of formula I and pharmaceutically acceptable salts thereof can be used as medicaments, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, drag ees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.

The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, drag ees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or aintioxidants. They can also contain still other therapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises by bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, a daily dosage of about 1 mg to 1000 mg should be appropriate.

Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutically usable salts thereof for the production of medicaments, especially for the control or prevention of illnesses which are caused by disorders of the dopamine system, is also an object of the invention.

EXAMPLE A

Tablets of the following composition are produced in the usual manner:

    ______________________________________                                                          mg/tablet                                                     ______________________________________                                         Active ingredient  100                                                         Powd. lactose      95                                                          White corn starch  35                                                          Polyvinylpyrrolidone                                                                               8                                                          Na carboxymethyl starch                                                                           10                                                          Magnesium stearate  2                                                          Tablet weight      250                                                         ______________________________________                                    

EXAMPLE B

Tablets of the following composition are produced in the usual manner:

    ______________________________________                                                          mg/tablet                                                     ______________________________________                                         Active ingredient  200                                                         Powd. lactose      100                                                         White corn starch   64                                                         Polyvinylpyrrolidone                                                                               12                                                         Na carboxymethyl starch                                                                            20                                                         Magnesium stearate  4                                                          Tablet weight      400                                                         ______________________________________                                    

EXAMPLE C

Capsules of the following composition are produced:

    ______________________________________                                                          mg/capsule                                                    ______________________________________                                         Active ingredient  50                                                          Cryst. lactose     60                                                          Microcrystalline cellulose                                                                        34                                                          Talc                5                                                          Magnesium stearate  1                                                          Capsule fill weight                                                                               150                                                         ______________________________________                                    

The active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatin capsules of suitable size. 

We claim:
 1. A method of treating or preventing an illness caused by a disorder of the dopamine system which comprises administering to a host in need of such treatment or prevention an effective amount of a pharmaceutical composition comprising a compound of the formula ##STR4## wherein R¹ and R³ each independently are hydrogen, aryl, carbamoyl, lower-alkyl-carbonyl, lower-alkyl, halogen, lower-alkyl-carbonyl-amino, lower-alkenyl-carbonyl-amino, amino, arylamino, aryloxy, nitro, aryl-acetyl, lower-alkanoyl-lower-alkyl, alkyl-sulphonyl-amino, ureido or furan-2-yl-carbonyl-amino andR² is hydrogen, lower-alkyl, trifluoromethyl, halogen, lower-alkoxy, lower-alkyl-carbonyl or lower-alkyl-carbonyl-amino or R¹ and R² together are --OCH₂ O--, --O(CH₂)₂ O-- or --(CH₂)₃ --, R⁴ is hydrogen, halogen, hydroxy, lower-alkyl, lower-alkoxy or nitro, R⁵ is hydrogen, halogen or lower-alkoxy, R⁶ is hydrogen, lower-alkyl, halogen, hydroxy, amino, lower-alkoxy, trifluoromethyl, nitro or lower-alkyl-carbonyl-amino and R⁷ is hydrogen or lower-alkyl-carbonyl,or a pharmaceutically acceptable salt of a compound of formula I, and a pharmaceutically inert carrier material.
 2. The method of claim 1, wherein R¹ is hydrogen or methyl, R² is hydrogen, trifluoromethyl or methyl, R⁴ is hydrogen, hydroxy or halogen, and R⁵ is hydrogen.
 3. The method of claim 1, wherein the illness is a psychotic illnesses.
 4. The method of claim 3, wherein the psychotic illness is schizophrenia.
 5. The method of claim 1, wherein the effective amount is 1 mg to 1000 mg per day. 